title: Synergistic antitumour activity of sorafenib in combination with tetrandrine is mediated by reactive oxygen species (ROS)/Akt signaling.
abstract: BACKGROUND
  Sorafenib is a potent inhibitor against Raf kinase and several receptor tyrosine kinases that has been approved for the clinical treatment of advanced renal and liver cancer. Combining sorafenib with other agents has been shown to improve its antitumour efficacy by not only reducing the toxic side effects but also preventing primary and acquired resistance to sorafenib. We have previously observed that tetrandrine exhibits potent antitumour effects in human hepatocellular carcinoma. In this study, we investigated the synergistic antitumour activity of sorafenib in combination with tetrandrine.
  
  
  METHODS
  This was a two-part investigation that included the in vitro effects of sorafenib in combination with tetrandrine on cancer cells and the in vivo antitumour efficacy of this drug combination on tumour xenografts in nude mice.
  
  
  RESULTS
  Combined treatment showed a good synergistic antitumour effect yet spared non-tumourigenic cells. The potential molecular mechanism may be mainly that it activated mitochondrial death pathway and induced caspase-dependent apoptosis in the cancer cells. Accumulation of intracellular reactive oxygen species (ROS) and subsequent activation of Akt may also be involved in apoptosis induction.
  
  
  CONCLUSIONS
  The antitumour activity of sorafenib plus tetrandrine may be attributed to the induction of the intrinsic apoptosis pathway through ROS/Akt signaling. This finding provides a novel approach that may broaden the clinical application of sorafenib.
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan, P R China.
authors.forename: J
authors.initials: J
authors.lastname: Wan
authors.forename: T
authors.initials: T
authors.lastname: Liu
authors.forename: L
authors.initials: L
authors.lastname: Mei
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.forename: K
authors.initials: K
authors.lastname: Gong
authors.forename: C
authors.initials: C
authors.lastname: Yu
authors.forename: W
authors.initials: W
authors.lastname: Li
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D044182:Benzylisoquinolines / Q000008:administration & dosage* / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004357:Drug Synergism; D045325:HCT116 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D051058:Oncogene Protein v-akt / Q000378:metabolism / Q000502:physiology; D010671:Phenylurea Compounds / Q000008:administration & dosage* / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D000077157:Sorafenib; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D044182:Benzylisoquinolines; D010671:Phenylurea Compounds; D017382:Reactive Oxygen Species; D009536:Niacinamide; C009438:tetrandrine; D000077157:Sorafenib; D051058:Oncogene Protein v-akt